Hypovitaminosis D is an important emerging risk factor for multiple sclerosis (MS). Because vitamin D deficiency is endemic worldwide, vitamin D supplementation offers a potentially high-impact strategy to reduce MS incidence. However, the role of vitamin D in MS risk likely varies by race/ethnicity and genetic background. These important relationships are poorly understood, which prevents a rational approach to developing global vitamin D supplementation policies. We propose to determine whether hypovitaminosis D is a more important risk factor for multiple sclerosis (MS) in certain subgroups, in particular those with darker skin or those who are genetically predisposed either to MS or hypovitaminosis D. To test these hypotheses, we propose to recruit 1000 individuals with incident MS including 250 African Americans and 330 Hispanics and 1000 matched control subjects from the multi-ethnic population of Kaiser Permanente Southern California (KPSC) members. The specific aims of the project are: 1) to determine whether hypovitaminosis D is associated with an increased risk of MS in African Americans and Hispanics; 2) to determine whether hypovitaminosis D is associated with an increased risk of MS in individuals who are positive for the main MS susceptibility allele, HLA-DRB1*15 compared with those who are negative for this allele (gene-environment interaction); and 3) to examine whether genetic determinants of hypovitaminosis D increase the risk of MS. The results of this study have the potential to guide global vitamin D supplementation policies and other MS prevention strategies and will improve our understanding of MS pathogenesis. The aims of this study cannot be addressed with any of the existing MS study populations because they consist predominantly of whites and lack information on vitamin D and/or genotype. This will be the first population-based study to examine the effect of hypovitaminosis D in non-white individuals, test for a gene-environment interaction between the main MS susceptibility allele and vitamin D and the first study to identify high-risk subgroups based on these factors. The proposed research addresses a critical barrier in developing global vitamin D supplementation policies and targeted interventions to prevent MS.